Fig. 3: Dynamics of DRB1 natural variants modulate DM susceptibility.
From: MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange
a, Exemplary MSM kinetic map of DRB1*01:01 and DRB1*04:01. Black discs represent metastable states (ground-state MS3 and two minor states MS1 (DM-susceptible) and MS2) with areas proportional to their relative stationary weights (maximum likelihood values). Black arrows indicate transitions between MSs, where the wider arrows indicate higher corresponding transition rates. Relative free energies and transition rates for the MSs are each shown with a superscript and subscript 1σ confidence interval (from bootstrapping trajectory MSMs). Each MS is illustrated by ribbon representations of MHC-II (white) and CLIP (magenta) of eight simulated conformations (one opaque, seven transparent, viewed from the top into the binding groove). The α-helices of α55–66 and β74-93 are highlighted in green and orange, respectively, with corresponding arrows indicating conformational changes with respect to the ground-state MS3. For localization of the DM interface (indicated by the red star), see Fig. 4. The kinetic maps for all of the other simulated allotypes are shown in Extended Data Fig. 4. b, Shown are individual data points of relative free energies (G) of MS1 (according to Fig. 3a and Extended Data Fig. 4) for allotypes in groups of low and high DM susceptibility (according to Fig. 2c). Bars represent the mean ± s.e.m. (group of low DM susceptibility (seven allotypes), 5.94 ± 0.92 kJ mol−1; group of high DM susceptibility (five allotypes), 2.36 ± 0.40 kJ mol−1). Data are plotted and analyzed (parametric two-sided t-test P value = 0.011, t = 3.1, d.f. = 10) with GraphPad Prism v9.3.1.
